Five people were killed in a crash on the R56 near Steynsburg and Middelburg in the Eastern Cape on Friday morning, Western Cape traffic chief Kenny Africa said.
Africa said another 10 people had been seriously injured, while another was slightly injured.
The road they had been travelling on is situated about 200km from the provincial borders of the Western and Eastern Cape.
It was closed as authorities inspected and managed the scene.
The cause of the accident and further details were not immediately available.
On Thursday, Africa issued an urgent plea for heightened awareness on the roads after several gruesome accidents in the Western Cape this week.
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"We cannot go on like this. Motorists need to take cognisance of the fact that road safety is not only the traffic [department] or the government's responsibility. It's everybody's responsibility," said Africa.
He called for respect for other road users, no unsafe overtaking, no using of cellphones, or texting while driving, and no drinking and driving.
Incidents of bad driving in the Western Cape can be reported to 021 946 1646.